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Alternative pathway androgen biosynthesis and human fetal female virilization
Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation....
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825302/ https://www.ncbi.nlm.nih.gov/pubmed/31611378 http://dx.doi.org/10.1073/pnas.1906623116 |
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author | Reisch, Nicole Taylor, Angela E. Nogueira, Edson F. Asby, Daniel J. Dhir, Vivek Berry, Andrew Krone, Nils Auchus, Richard J. Shackleton, Cedric H. L. Hanley, Neil A. Arlt, Wiebke |
author_facet | Reisch, Nicole Taylor, Angela E. Nogueira, Edson F. Asby, Daniel J. Dhir, Vivek Berry, Andrew Krone, Nils Auchus, Richard J. Shackleton, Cedric H. L. Hanley, Neil A. Arlt, Wiebke |
author_sort | Reisch, Nicole |
collection | PubMed |
description | Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenals, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography–tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography–mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. |
format | Online Article Text |
id | pubmed-6825302 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-68253022019-11-06 Alternative pathway androgen biosynthesis and human fetal female virilization Reisch, Nicole Taylor, Angela E. Nogueira, Edson F. Asby, Daniel J. Dhir, Vivek Berry, Andrew Krone, Nils Auchus, Richard J. Shackleton, Cedric H. L. Hanley, Neil A. Arlt, Wiebke Proc Natl Acad Sci U S A Biological Sciences Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenals, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography–tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography–mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. National Academy of Sciences 2019-10-29 2019-10-14 /pmc/articles/PMC6825302/ /pubmed/31611378 http://dx.doi.org/10.1073/pnas.1906623116 Text en Copyright © 2019 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Reisch, Nicole Taylor, Angela E. Nogueira, Edson F. Asby, Daniel J. Dhir, Vivek Berry, Andrew Krone, Nils Auchus, Richard J. Shackleton, Cedric H. L. Hanley, Neil A. Arlt, Wiebke Alternative pathway androgen biosynthesis and human fetal female virilization |
title | Alternative pathway androgen biosynthesis and human fetal female virilization |
title_full | Alternative pathway androgen biosynthesis and human fetal female virilization |
title_fullStr | Alternative pathway androgen biosynthesis and human fetal female virilization |
title_full_unstemmed | Alternative pathway androgen biosynthesis and human fetal female virilization |
title_short | Alternative pathway androgen biosynthesis and human fetal female virilization |
title_sort | alternative pathway androgen biosynthesis and human fetal female virilization |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825302/ https://www.ncbi.nlm.nih.gov/pubmed/31611378 http://dx.doi.org/10.1073/pnas.1906623116 |
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